Abstract
Premature aging syndromes are rare genetic disorders mimicking clinical and molecular features of aging. Products of the LMNA gene, primarily lamin A and C, are major components of the nuclear lamina. A recently identified group of premature aging syndromes was related to mutations of the LMNA gene. Although LMNA disorders have been identified in premature aging syndromes, affect specifically the skeletal muscles, cardiac muscles, and lipodystrophy, understanding the pathogenic mechanisms still need to be elucidated. Here, to establish a rabbit knockout (KO) model of premature aging syndromes, we performed precise LMNA targeting in rabbits via co-injection of Cas9/sgRNA mRNA into zygotes. The LMNA-KO rabbits exhibited reduced locomotion activity with abnormal stiff walking posture and a shortened stature, all of them died within 22 days. In addition, cardiomyopathy, muscular dystrophy, bone and joint abnormalities, as well as lipodystrophy were observed in LMNA-KO rabbits. In conclusion, the novel rabbit LMNA-KO model, displayed typical features of histopathological defects that are observed in premature aging syndromes, and may be utilized as a valuable resource for understanding the pathophysiological mechanisms of premature aging syndromes and elucidating mysteries of the normal process of aging in humans.
Highlights
Premature aging syndromes are rare genetic disorders mimicking clinical and molecular features of aging
A rabbit model of lamin A (LMNA) deficiency generated by CRISPR/Cas9 reported that mutations in the LMNA gene are associated with a wide range of human genetic disorders, including dilated cardiomyopathy with conduction-system disease (DCM-CD) [8], limb girdle muscular dystrophy with atrioventricular conduction disturbance (LGMD1B) [9], Dunnigan-type of familial partial lipodystrophy [10], autosomal recessive Charcot-Marie-Tooth disease type 2 [11], mandibuloacral dysplasia[12], Hutchinson-Gilford progeria syndrome (HGPS) [13, 14], atypical Werner’s syndrome [15], and restrictive dermopathy [16]
No significant differences were observed in the developmental rate between non-injected embryos and CRISPR/Cas9-injected embryos (p > 0.05), indicating that the microinjection process itself had little to no impact on the development of the rabbit embryo
Summary
Premature aging syndromes are rare genetic disorders mimicking clinical and molecular features of aging. A rabbit model of LMNA deficiency generated by CRISPR/Cas reported that mutations in the LMNA gene are associated with a wide range of human genetic disorders, including dilated cardiomyopathy with conduction-system disease (DCM-CD) [8], limb girdle muscular dystrophy with atrioventricular conduction disturbance (LGMD1B) [9], Dunnigan-type of familial partial lipodystrophy [10], autosomal recessive Charcot-Marie-Tooth disease type 2 [11], mandibuloacral dysplasia[12], Hutchinson-Gilford progeria syndrome (HGPS) [13, 14], atypical Werner’s syndrome [15], and restrictive dermopathy [16]. LmnaL530P/L530P mice showed clinical defects that were consistent with human HGPS, including a reduction in growth rate, pathologies of the bone, muscle and death by 4 weeks of age [20] These mouse models failed to recapitulate several features of the premature aging syndrome from the gene mutation to the clinic. There is a need to develop premature aging syndrome models in species other than the mouse, which recapitulate human premature aging syndrome with reasonable costs for ordinary laboratory
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